Clinical and cytological studies are proposed in six genetically determined human disorders: Bloom's syndrome (BS), Fanconi's anemia (FA), ataxia telangiectasia (AT), xeroderma pigmentosum (XP), Werner's syndrome (WS), and Robert's syndrome (RS). Developmental defects exist at the organismal and, or, cellular level in each syndrome: BS is characterized by severe intra- and extra-uterine growth deficiency and often by immunodeficiency; skeletal and renal abnormalities and marrow failure are present in FA; in AT immunodeficiency exists; neurological deficiencies occur in some complementation groups in XP; in WS many features of aging appear prematurely; growth deficiency and tetraphocomelia are features of RS. Growth distrurbances exist also in cultured cells from most of the disorders. A common cytogenetic feature of all six syndromes is chromosome instability and, with the exception of RS, an increased incidence of cancer. The chromosome instability in BS, FA, AT, and XP exists in the form of significantly increased numbers of broken and rearranged chromosomes occurring either spontaneously of following treatment with DNA damaging agents, while in RS premature separation of the heterochromatic chromosome regions occurs. Specific aims of the proposed research are the following: (i) The clinical features and genetics of the six syndromes will be defined more fully. Affected families will be followed for years to come, determining particularly the incidence, age of onset, and types of cancer that occur in homo- and heterozygotes. (ii) The in vitro growth disturbances in cells from persons with the syndromes will be characterized looking particularly for a block in some cell cycle stage. (iii) The emergence, evolution, and expansion of clones of cell shaving mutated chromosome complements will be followed trying to correlate their presence with such clinical changes as the development of cancer and immunodeficiency. (iv) Evidence will be sought for genome instability in vivo by looking for an increased incidence of mutation.